tbuckley/cabot-search huggingface dataset:
Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease
Authors: Matthew Moll, Joanne E. Sordillo, Auyon J. Ghosh, Lystra P. Hayden, Gregory McDermott, Michael J. McGeachie, Amber Dahlin, Anshul Tiwari, Monica G. Manmadkar, Eric D. Abston, Chandan Pavuluri, Aabida Saferali, Sofina Begum, John P. Ziniti, Amund Gulsvik, Per S. Bakke, Hugues Aschard, Carlos Iribarren, Craig P. Hersh, Jeffrey A. Sparks, Brian D. Hobbs, Jessica A. Lasky-Su, Edwin K. Silverman, Scott T. Weiss, Ann Chen Wu, Michael H. Cho
Journal: Journal of Allergy and Clinical Immunology (2023)
A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors
Authors: Sami Boudkkazi, Jochen Schwenk, Naoki Nakaya, Aline Brechet, Astrid Kollewe, Harumi Harada, Wolfgang Bildl, Akos Kulik, Lijin Dong, Afia Sultana, Gerd Zolles, Uwe Schulte, Stanislav Tomarev, Bernd Fakler
Journal: Neuron (2023)

Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that distribution and dynamics of AMPARs in the plasma membrane are controlled by Noelins, a three-member family of conserved secreted proteins expressed throughout the brain in a cell-type-specific manner. Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. Our results uncover an endogenous mechanism for extracellular anchoring of AMPARs and establish Noelin-organized networks as versatile determinants of constitutive and context-dependent neurotransmission.
CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression
Authors: Kristan Meetze, Naveen K Mehta, Bochong Li, Hannah M Findlay, Timothy B London, Agapitos Patakas, Jennifer S Michaelson, Patrick A Baeuerle
Journal: Journal for ImmunoTherapy of Cancer (2023)

Despite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.To address this issue, we have developed a 65-kDa multispecific antibody construct, CLN-978, with affinities tuned to optimize the killing of low-CD19 expressing tumor cells. CLN-978 bound to CD19 on B cells with picomolar affinity, and to CD3ε on T cells with nanomolar affinity. A serum albumin binding domain was incorporated to extend serum half-life. In this setting, we biophysically characterize and report the activities of CLN-978 in cell co-culture assays, multiple mouse models and non-human primates.Human T cells redirected by CLN-978 could eliminate target cells expressing less than 300 copies of CD19 on their surface. The half-life extension and high affinity for CD19 led to significant antitumor activity in murine lymphoma models at very low doses of CLN-978. In primates, we observed a long serum half-life, deep and sustained depletion of normal B cells, and remarkable tolerability, in particular, reduced cytokine release when CLN-978 was administered subcutaneously.CLN-978 warrants further exploration. An ongoing clinical phase 1 trial is investigating safety, pharmacokinetics, pharmacodynamics, and the initial therapeutic potential of subcutaneously administered CLN-978 in patients with non-Hodgkin's lymphoma.
Association between Residential Greenness and Human Microbiota: Evidence from Multiple Countries
Authors: Yi-Dan Zhang, Shu-Jun Fan, Zheng Zhang, Jia-Xin Li, Xiao-Xuan Liu, Li-Xin Hu, Luke D. Knibbs, Payam Dadvand, Bin Jalaludin, Matthew H.E.M. Browning, Tianyu Zhao, Joachim Heinrich, Zhini He, Cheng-Zhi Chen, Yuanzhong Zhou, Guang-Hui Dong, Bo-Yi Yang
Journal: Environmental Health Perspectives (2023)

BACKGROUND: Greenness, referring to a measurement of the density of vegetated land (e.g., gardens, parks, grasslands), has been linked with many human health outcomes.However, the evidence on greenness exposure and human microbiota remains limited, inconclusive, drawn from specific regions, and based on only modest sample size.OBJECTIVES: We aimed to study the association between greenness exposure and human microbial diversity and composition in a large sample across 34 countries and regions.METHODS: We explored associations between residential greenness and human microbial alpha-diversity, composition, and genus abundance using data from 34 countries.Greenness exposure was assessed using the normalized difference vegetation index and the enhanced vegetation index mean values in the month before sampling.We used linear regression models to estimate the association between greenness and microbial alpha-diversity and tested the effect modification of age, sex, climate zone, and pet ownership of participants.Differences in microbial composition were tested by permutational multivariate analysis of variance based on Bray-Curtis distance and differential taxa were detected using the DESeq2 R package between two greenness exposure groups split by median values of greenness.RESULTS: We found that higher greenness was significantly associated with greater richness levels in the palm and gut microbiota but decreased evenness in the gut microbiota.Pet ownership and climate zone modified some associations between greenness and alpha-diversity.Palm and gut microbial composition at the genus level also varied by greenness.Higher abundances of the genera Lactobacillus and Bifidobacterium, and lower abundances of the genera Anaerotruncus and Streptococcus, were observed in people with higher greenness levels.DISCUSSION: These findings suggest that residential greenness was associated with microbial richness and composition in the human skin and gut samples, collected across different geographic contexts.Future studies may validate the observed associations and determine whether they correspond to improvements in human health.
Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma
Authors: Neslihan Arife Kaya, David Tai, Xinru Lim, Jia Qi Lim, Mai Chan Lau, Denise Goh, Cheryl Zi Jin Phua, Felicia Yu Ting Wee, Craig Ryan Joseph, Jeffrey Chun Tatt Lim, Zhen Wei Neo, Jiangfeng Ye, Lawrence Cheung, Joycelyn Lee, Kelvin S H Loke, Apoorva Gogna, Fei Yao, May Yin Lee, Timothy Wai Ho Shuen, Han Chong Toh, Axel Hilmer, Yun Shen Chan, Tony Kiat-Hon Lim, Wai Leong Tam, Su Pin Choo, Joe Yeong, Weiwei Zhai
Journal: Journal for ImmunoTherapy of Cancer (2023)

Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown. By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial. We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy. This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.
ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Authors: Jacqueline E Mann, Liliana Lucca, Matthew R Austin, Ross D Merkin, Marie E Robert, Badr Al Bawardy, Khadir Raddassi, Lilach Aizenbud, Nikhil S Joshi, David A Hafler, Clara Abraham, Kevan C Herold, Harriet M Kluger
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors (ICIs) are increasingly being used to manage multiple tumor types. Unfortunately, immune-related adverse events affect up to 60% of recipients, often leading to treatment discontinuation in settings where few alternative cancer therapies may be available. Checkpoint inhibitor induced colitis (ICI-colitis) is a common toxicity for which the underlying mechanisms are poorly defined. To better understand the changing colon-specific and peripheral immune environments over the course of progression and treatment of colitis, we collected blood and colon tissue from a patient with Merkel cell carcinoma who developed colitis on treatment with pembrolizumab. We performed single-cell RNA sequencing and T-cell receptor sequencing on samples collected before, during and after pembrolizumab and after various interventions to mitigate toxicity. We report T-cells populations defined by cytotoxicity, memory, and proliferation markers at various stages of colitis. We show preferential depletion of CD8+ T cells with biologic therapy and nominate both circulating and colon-resident T-cell subsets as potential drivers of inflammation and response to immune suppression. Our findings highlight the need for further exploration of the colon immune environment and rationalize future studies evaluating biologics for ICI-colitis, including in the context of ICI re-challenge.
Reactivation of low avidity tumor-specific CD8<sup>+</sup>T cells associates with immunotherapeutic efficacy of anti-PD-1
Authors: Gessa Sugiyarto, Doreen Lau, Samuel Luke Hill, David Arcia-Anaya, Denise S M Boulanger, Eileen E Parkes, Edward James, Tim Elliott
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background CD8 + T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8 + specificities and TCR avidity of naturally arising tumor-specific T cells, where both high and low avidity T cells recognizing the same peptide-major histocompatibility complex (pMHC) coexist in the same tumor, are crucial for understanding T cell exhaustion and resistance to PD-1 immunotherapy. Methods CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8 + T cells targeting the tumor-specific epitope GSW11 and confirmed with tetramer competition assays. Functional characterization of high and low avidity GSW11-specific CD8 + T cells was conducted using flow cytometry and bulk RNA-seq. In vitro cytotoxicity assays and in vivo adoptive transfer experiments were performed to determine the cytotoxicity of high and low avidity populations. Results Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tet lo ) GSW11-specific CD8 + T cells with Vβ TCR expressing clonotypes. High avidity T cells (Tet hi ), if present, were only found in progressing PD-1 refractory tumors. Tet lo demonstrated precursor exhausted or progenitor T cell phenotypes marked by higher expression of Tcf-1 and T-bet, and lower expression of the exhaustion markers CD39, PD-1 and Eomes compared with Tet hi , whereas Tet hi cells were terminally exhausted. Transcriptomics analyses showed pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly enriched in Tet lo found in both regressing and progressing tumors compared with Tet hi , whereas genes related to DNA damage, apoptosis and autophagy were downregulated. In vitro studies showed that Tet lo exhibits higher cytotoxicity than Tet hi . Adoptive transfer of Tet lo showed more effective tumor control than Tet hi , and curative responses were achieved when Tet lo was combined with two doses of anti-PD-1. Conclusions Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer.
Personalized neoantigen viro-immunotherapy platform for triple-negative breast cancer
Authors: Renato Brito Baleeiro, Peng Liu, Louisa S Chard Dunmall, Carmela Di Gioia, Ai Nagano, Lauren Cutmore, Jun Wang, Claude Chelala, Lydon Wainaina Nyambura, Peter Walden, Nicholas Lemoine, Yaohe Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV). We used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients' samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival. We successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival. Our study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials.
Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden
Authors: Vaia Florou, Charalampos S Floudas, Asaf Maoz, Abdul Rafeh Naqash, Carter Norton, Aik Choon Tan, Ethan S Sokol, Garrett Frampton, Heloisa P Soares, Sonam Puri, Umang Swami, Breelyn Wilky, Peter Hosein, Jonathan Trent, Gilberto de Lima Lopes, Wungki Park, Ignacio Garrido-Laguna
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients. Methods Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups. Results We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (&lt;10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p&lt;0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A. Conclusions FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.
Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin
Authors: Zhijie Zhang, Chang Liu, Muhan Wang, Rongcheng Sun, Zhe Yang, Zhen Hua, Yushuang Wu, Mengting Wu, Hang Wang, Wen Qiu, Hongping Yin, Meijia Yang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth. We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models. Methods Results In the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion. Conclusion Our study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors.
Mixtures of Metals and Micronutrients in Early Pregnancy and Cognition in Early and Mid-Childhood: Findings from the Project Viva Cohort
Authors: Ruwan Thilakaratne, Pi-I D. Lin, Sheryl L. Rifas-Shiman, Robert O. Wright, Alan Hubbard, Marie-France Hivert, David Bellinger, Emily Oken, Andres Cardenas
Journal: Environmental Health Perspectives (2023)

Background: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. Objectives: Our aim was to evaluate associations of first-trimester (∼10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (∼3 y) and mid-childhood (∼8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. Methods: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the "nutrient mixture," as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the "neurotoxic mixture," in first-trimester (∼10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (∼3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (∼8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. Results: Analyses included 900 mother–child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of −3.01 points (95% CI: −5.55, −0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. Discussion: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. https://doi.org/10.1289/EHP12016